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J. Biol. Chem. 278 (2): 1044-1052

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Antidepressant-induced Switch of beta 1-Adrenoceptor Trafficking as a Mechanism for Drug Action*

Sibylle Bürgi, Kurt Baltensperger, and Ulrich E. HoneggerDagger

From the Department of Pharmacology, University of Bern, CH-3010 Bern, Switzerland

Reduction in surface beta 1-adrenoceptor (beta 1AR) density is thought to play a critical role in mediating the therapeutic long term effects of antidepressants. Since antidepressants are neither agonists nor antagonists for G protein-coupled receptors, receptor density must be regulated through processes independent of direct receptor activation. Endocytosis and recycling of the beta 1AR fused to green fluorescent protein at its carboxyl-terminus (beta 1AR-GFP) were analyzed by confocal fluorescence microscopy of live cells and complementary ligand binding studies. In stably transfected C6 glioblastoma cells, beta 1AR-GFP displayed identical ligand-binding isotherms and adenylyl cyclase activation as native beta 1AR. Upon exposure to isoproterenol, a fraction of beta 1AR-GFP (10-15%) internalized rapidly and colocalized with endocytosed transferrin receptors in an early endosomal compartment in the perinuclear region. Chronic treatment with the tricyclic antidepressant desipramine (DMI) did not affect internalization characteristics of beta 1AR-GFP when challenged with isoproterenol. However, internalized receptors were not able to recycle back to the cell surface in DMI-treated cells, whereas recycling of transferrin receptors was not affected. Endocytosed receptors were absent from structures that stained with fluorescently labeled dextran, and inhibition of lysosomal protease activity did not restore receptor recycling, indicating that beta 1AR-GFP did not immediately enter the lysosomal compartment. The data suggest a new mode of drug action causing a "switch" of receptor fate from a fast recycling pathway to a slowly exchanging perinuclear compartment. Antidepressant-induced reduction of receptor surface expression may thus be caused by modulation of receptor trafficking routes.


* This study was supported by Swiss National Science Foundation Grants 32-47029.96 (to U. H.) and 3100-059124.99 (to K. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Pharmacology, University of Bern, Friedbuehlstr. 49, CH-3010 Bern, Switzerland. Tel.: 41-31-632-3281; Fax: 41-31-632-4992; E-mail: ulrich.honegger@pki.unibe.ch.


Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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